Method for the production of tetrakis(trihydrocarbyl phosphane)palladium(0)

ABSTRACT

Method for the production of tetrakis(trihydrocarbylphosphane)palladium(0) in organic solvent, whereby 50 to 100% by weight of the organic solvent consist of at least one polar-aprotic solvent, characterised in that a) at least one palladium compound selected from the group consisting of palladium(II) compounds and palladium(IV) compounds that are soluble in the organic solvent is reacted with b) at least one base, selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal-C1-C4-alcoholates, ammonium carbonate, ammonium hydrogen carbonate, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrogen carbonates, alkaline earth metal-C1-C4-alcoholates, and alkylamines with a total of 2 to 12 carbon atoms; c) at least one trihydrocarbylphosphane; and d) at least one organic reducing agent that is different from the remaining components that are used in the method.

Transition metal-catalysed cross coupling reactions for linking, mainly,unsaturated C-atoms have become indispensable in modern organicchemistry. Examples to be mentioned here include the Suzuki coupling forthe production of agents, such as the antibiotic vancomycin, or theStille coupling for the production of conjugated polymers. Pd(0)complexes are by far the most frequently used transition metal catalystsfor this purpose. Palladium(0)-triarylphosphane complexes, such astetrakis(triphenylphosphane)palladium(0), are an important class ofPd(0) complexes.

The synthesis of tetrakis(triphenylphosphane)palladium(0) is known fromCoulson, Tetrakis(triphenylphosphine)palladium(0), Inorganic Synthesis;1972, pages 121-123. Here, starting from PdCl₂ and PPh₃ in DMSO solutionand hydrazine hydrate, the tetrakis(triphenylphosphane)palladium complexwith Pd in oxidation state (0) is obtained. Since hydrazine hydrate andother hydrazine derivatives are toxic and can be carcinogenic, there arecontinuing efforts to replace hydrazine hydrate and derivatives asreactants in order to improve the occupational safety.

WO 2010/128316 describes a hydrazine hydrate-free production procedure,in which a Pd(II) compound is reacted in at least one solvent containinga base and a ligand L (PPh₃). The yields typically range from 66 to 93%.

It was the object of the present invention to develop a method for theproduction of tetrakis(trihydrocarbylphosphane)palladium(0), whichprovides for the highest possible yield and forgoes the use of hydrazinehydrate.

To this end, a method is provided, in which Pd(II) and/or Pd(IV)compounds in organic solvent are reacted with at least onetrihydrocarbylphosphane ligand through the aid of at least one base andat least one organic reducing agent.

Specifically, the object is met by a method for the production oftetrakis(trihydrocarbylphosphane)palladium(0) in organic solvent,whereby 50 to 100% by weight of the organic solvent consist of at leastone polar-aprotic solvent, characterised in that

-   -   a) at least one palladium compound selected from the group        consisting of palladium(II) compounds and palladium(IV)        compounds that are soluble in the organic solvent is reacted        with    -   b) at least one base, selected from the group consisting of        alkali metal hydroxides, alkali metal carbonates, alkali metal        hydrogen carbonates, alkali metal-C₁-C₄-alcoholates, ammonium        carbonate, ammonium hydrogen carbonate, alkaline earth metal        hydroxides, alkaline earth metal carbonates, alkaline earth        metal hydrogen carbonates, alkaline earth        metal-C₁-C₄-alcoholates, and alkylamines with a total of 2 to 12        carbon atoms;    -   c) at least one trihydrocarbylphosphane; and    -   d) at least one organic reducing agent that is different from        the remaining components that are used in the method.

The terms “alkali metal” and “alkaline earth metal” that are used in thecontext of component b) and, further on, in the context of component d),stand for lithium, sodium, and potassium or magnesium, calcium, andbarium, respectively.

Through the use of the present method,tetrakis(trihydrocarbylphosphane)palladium(0) can be produced withoutthe use of hydrazine hydrate at yields in excess of 95%, relative to thepalladium in the at at least one palladium compound that is used in themethod.

The at least one, preferably only one, palladium compound can beselected from palladium compounds in oxidation states (II) and (IV) thatare soluble in the organic solvent. Preferably, the at least onepalladium compound is a compound selected from the group consisting ofalkali tetrahalogenopalladates(II), ammoniumtetrahalogenopalladates(II), alkali hexahalogenopalladates(IV), ammoniumhexahalogenopalladates(IV), palladium(II) halides, palladium(II)nitrate, palladium(II) sulfate,bis(trihydrocarbylphosphane)palladium(II) dihalides, Pd(COD)Cl₂(COD=cyclooctadiene), Pd(CH₃CN)₂Cl₂, Pd(C₆H₅CN)₂Cl₂, and palladium(II)acetate.

The halides can be chlorine, bromine or iodine, in particular chlorineor bromine. In a preferred embodiment, the palladium compound is PdCl₂.

Used in the context of the alkali tetrahalogenopalladates(II) and thealkali hexahalogenopalladates(IV) of component a), the term “alkali”stands for sodium or potassium. According to the invention, the organicsolvent comprises at least one, preferably only one, polar-aproticorganic solvent in an amount of 50 to 100% by weight, in particular inan amount of 90 to 100% by weight, specifically 100% by weight. In thecontext of the present invention, a solvent shall be understood to be“polar” if it has an E_(T)(30) value of 150 kJ/mol or more. Thepolar-aprotic solvent preferably has an E_(T)(30) value of 170 kJ/mol ormore (referring to E_(T)(30) values, see C. Reichardt, Chem. Rev. 1994,94, 2319-2358). Preferred polar-aprotic solvents are selected from thegroup consisting of tertiary carboxylic acid amides (e.g., DMF),sulfoxides (e.g., DMSO), ketones (e.g., acetone), lactones (e.g.,gamma-butyrolactone), lactams (e.g., N-methyl-2-pyrrolidone), nitriles(e.g., acetonitrile), urea derivatives, sulf ones, carboxylic acidesters (e.g., acetic acid ethyl ester), and carbonic acid esters. DMF,DMSO, acetone, gamma-butyrolactone, N-methyl-2-pyrrolidone, acetic acidethyl ester, and acetonitrile are particularly preferred.

Aside from the at least one polar-aprotic organic solvent, one or moreadditional organic solvents that are miscible with the at least onepolar-aprotic solvent can be used as well. Said additional organicsolvents can be selected from the group of the polar-protic solvents(e.g., alcohols) and the apolar solvents (such as, e.g., pentane,hexane, heptane, benzene, toluene, xylene). Alcohols such as, e.g.,methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,tert-butanol, and benzylalcohol are preferred polar-protic solvents. Theadditional organic solvent(s) account(s) for 0 to 50% by weight, inparticular 0 to 10% by weight, specifically 0% by weight of the totalorganic solvent according to the above-mentioned specifications for theat least one polar-aprotic solvent.

The at least one, preferably only one, base can be selected from thegroup consisting of alkali metal hydroxides, alkali metal carbonates,alkali metal hydrogen carbonates, alkali metal-C₁-C₄-alcoholates,ammonium carbonate, ammonium hydrogen carbonate, alkaline earth metalhydroxides, alkaline earth metal carbonates, alkaline earth metalhydrogen carbonates, alkaline earth metal-C₁-C₄-alcoholates, andalkylamines with a total of 2 to 12 carbon atoms. Hydroxides, inparticular alkali metal hydroxides, such as, e.g., sodium hydroxide,hydrogen carbonates, in particular alkali metal hydrogen carbonates,such as, e.g., sodium hydrogen carbonate, alkali metal carbonates, suchas, e.g., sodium carbonate, and trialkylamines, such as, e.g.,triethylamine, are preferred.

Alkali metal hydroxides, such as, e.g., sodium hydroxide, hydrogencarbonates, in particular alkali metal hydrogen carbonates, such as,e.g., sodium hydrogen carbonate, alkali metal carbonates, such as, e.g.,sodium carbonate, and triethylamine, specifically the inorganic bases,i.e. the alkali metal hydroxides, such as, e.g., sodium hydroxide, thehydrogen carbonates, in particular the alkali metal hydrogen carbonates,such as, e.g., sodium hydrogen carbonate, the alkali metal carbonates,such as, e.g., sodium carbonate, are particularly preferred.

In one embodiment, the at least one, preferably only one, organicreducing agent is selected from the group consisting of ascorbic acid,formic acid, as well as alkali metal, alkaline earth metal and ammoniumsalts of said acids, phenols with a reducing effect, such as, e.g.,hydroquinone, catechol, resorcinol, pyrogallol, hydroxyhydroquinone,phenol derivatives with a reducing effect and sugars with a reducingeffect, such as, e.g., mono-, di- or oligosaccharides. Particularlypreferred sugars with a reducing effect are mannose, glucose, fructose,maltose, lactose, and galactose. Ascorbic acid and formic acid, inparticular ascorbic acid, are preferred as organic reducing agents. Theat least one organic reducing agent differs from the remainingcomponents that are used in the method according to the invention(including organic solvents as well as components a) to c)).

The three hydrocarbyl residues of the at least one, preferably only one,trihydrocarbylphosphane can be selected from the group consisting ofunsubstituted and substituted aryl residues, open chain alkyl residues,and cyclic alkyl residues, in any combination thereof. Preferably, thetrihydrocarbylphosphane comprises three identical hydrocarbyl residues.Substituted aryl residues of the trihydrocarbylphosphanes can each bemono-, di- or tri-substituted. Alkyl substituents with 1-10 carbon atomsare preferred.

In one embodiment, this concerns trialkylphosphanes with three alkylresidues each of which comprises 1-10 carbon atoms. The alkyl residuesof the trialkylphosphanes can be identical or different from each other.Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclohexyl andadamantyl residues, in particular ethyl, n-propyl, isopropyl, n-butyl,tert-butyl and cyclohexyl residues are preferred alkyl residues of saidtrialkylphosphanes.

One preferred embodiment concerns triarylphosphanes, in particularunsubstituted triphenylphosphane.

Besides, the trihydrocarbylphosphanes can just as well be selected fromthe group consisting of: phenyl-di-tert-butylphosphane,di-tert-butyl-neopentylphosphane, tricyclohexylphosphane,di(tert-butyl)phosphane, tris(para-tolyl)phosphane,tris(ortho-tolyl)phosphane, tris(2,4,6,-trimethylphenyl)phosphane,tris(2,6-dimethylphenyl)phosphane, 1-adamantyl-di-tert-butylphosphane,benzyl-di-1-adamantylphosphane, n-butyl-di-1-adamantylphosphane,cyclohexyl-di-(tert-butyl)phosphane, cyclohexyl-diphenylphosphane.

A preferred embodiment of the present invention is a method for theproduction of tetrakis(trihydrocarbylphosphane)palladium(0) in organicsolvent that consists of 50 to 100% by weight, preferably 100% byweight, of at least one polar-aprotic solvent selected from the groupconsisting of DMF, DMSO, acetone, gamma-butyrolactone,N-methyl-2-pyrrolidone, acetic acid ethyl ester, and acetonitrile, inparticular of 50 to 100% by weight, preferably 100% by weight, DMSO,characterised in that

-   -   A) at least one palladium compound selected from the group        consisting of alkali tetrahalogenopalladates(II), ammonium        tetrahalogenopalladates(II), alkali hexahalogenopalladates(IV),        ammonium hexahalogenopalladates(IV), palladium(II) halides,        palladium(II) nitrate, palladium(II) sulfate,        bis(trihydrocarbylphosphane)palladium(II) dihalides, Pd(COD)Cl₂        (COD=cyclooctadiene), Pd(CH₃CN)₂Cl₂, Pd(C₆H₅CN)₂Cl₂, and        palladium(II) acetate, in particular PdCl₂, is reacted with    -   b) at least one base, selected from the group consisting of        alkali metal hydroxides, alkali metal carbonates, alkali metal        hydrogen carbonates, and triethylamine, but selected        particularly from the group consisting of alkali metal        hydroxides, alkali metal carbonates, and alkali metal hydrogen        carbonates;    -   c) at least one trihydrocarbylphosphane, in particular        triphenylphosphane; and    -   d) at least one reducing agent selected from the group        consisting of formic acid, ascorbic acid as well as alkali        metal, alkaline earth metal, and ammonium salts of said acids,        but, in particular, ascorbic acid.

In order to attain particularly high yields, it is preferred toimplement the method according to the invention in an inert gasatmosphere. The inert gas can comprise, e.g., nitrogen or argon.

The at least one reducing agent is used, relative to palladium, forexample, in an amount equal to 1- to 3-fold of the equivalent amountrequired for reduction to palladium(0).

For example, 2-4 molar equivalents of base are used per molar equivalentof palladium(II), or, for example, 4-8 molar equivalents of base areused per molar equivalent of palladium(IV).

It is preferred to use the at least one trihydrocarbylphosphane in anamount equal to 4- to 6-fold of the molar equivalent, relative topalladium.

The concentration of the palladium used this context, relative to theorganic solvent, can be in the range of, for example, 0.05 mol/L to 0.25mol/L, preferably in the range of 0.10 mol/L to 0.15 mol/L.

Preferably, the method of the present invention is a one-pot reaction.Usually, the organic solvent will be added first and the reactants areadded into the solvent.

The reaction temperature can be in the range of 45 to 80° C., inparticular in the range of 55 to 70° C.

The purification can take place according to methods that are familiarto a person skilled in the art, for example without a need for extensivecleaning procedures. Accordingly, thetetrakis(trihydrocarbylphosphane)palladium(0) thus produced can beseparated as a solid from the liquid phase, e.g. by filtration,centrifugation or decanting. The separated solid can be washed withwater. After this may follow further washing steps with water-misciblealcohols (e.g. isopropanol) and then with alkanes (i.e. petroleumether). Subsequently, the product can be dried at reduced pressure.

The method according to the invention can be used to producetetrakis(trihydrocarbylphosphane)palladium(0) complexes at high yieldwithout the use of hydrazine hydrate. In particular, yields of 95% ormore relative to the palladium in the at least one palladium compoundused in the method are readily attainable by the method of the presentinvention.

EXAMPLES Example 1

Approx. 215 g DMSO, 5.032 g PdCl₂ (Pd 3.000 g, 28.19 mmol), 37.5 g PPh₃(PPh₃ 143.13 mmol) and 9.9 g formic acid (C₆H₈O₆ 56.25 mmol) and 6.6 gNaHCO₃ (78.56 mmol) were placed in a 4-necked flask, and approx. 10 gDMSO were used for rinsing. Subsequently, the mixture was stirred atroom temperature for 20 minutes. Then, the suspension was heated to aninternal temperature of 60° C. Once the temperature was reached, themixture had a bright yellow colour.

After stirring for a period of 2 hours at 60° C., the sample was cooledpassively to room temperature (22° C.).

The suspension was transferred through a Teflon hose by means of argoninto a Schlenk frit (G3 frit) made inert with argon, and then filtered.The content of the flask was rinsed with 15 g of DMSO and then alsotransferred to the frit. This resulted in a bright red filtrate and abright yellow filter cake.

The product on the Schlenk frit was washed with 4×80 g fully de-saltedwater, 3×30 g isopropanol, and 3×20 g petroleum spirit. The filter cakewas dried for approximately 40 minutes at reduced pressure.

This resulted in a bright yellow powder.

The product was then tested for its palladium content. Moreover, an IRspectrum was measured and an elemental analysis was performed.

Product=32.003 g

Pd content=9.15% by weight (gravimetric determination in triplicate,theoretical value 9.20 wt.-%)

Pd=2.92 g (added: 3.00 g)

Yield=97.6% relative to the palladium in the PdCl₂ used here

IR: corresponds to the reference spectrum for pure Pd(PPh₃)₄

Elemental analysis: expected for Pd(PPh₃)₄ C, 74.84%, H, 5.23%, O, 0%,P, 10.72%; detected C, 74.30%, H, 5.35%, O<0.2%, P, 10.55%.

Examples 2-4

Three other experiments were run analogous to Example 1. The onlydifference being the type of base that was used, while all othersubstances and molar amounts of substances were kept unchanged:

Example 1 2 3 4 Base NaHCO₃ KOH Na₂CO₃ NEt₃ Palladium compound PdCl₂Reducing agent Ascorbic acid Trihydrocarbylphosphane TriphenylphosphaneSolvent DMSO Yield (by ³¹P-NMR 100% 98% 100% 100% spectroscopy)

1. A method for the production oftetrakis(trihydrocarbylphosphane)palladium(0) in organic solvent,whereby 50 to 100% by weight of the organic solvent consists of at leastone polar-aprotic solvent, wherein a) at least one palladium compoundselected from the group consisting of palladium(II) compounds andpalladium(IV) compounds that are soluble in the organic solvent isreacted with b) at least one base, selected from the group consisting ofalkali metal hydroxides, alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal-C₁-C₄-alcoholates, ammonium carbonate, ammoniumhydrogen carbonate, alkaline earth metal hydroxides, alkaline earthmetal carbonates, alkaline earth metal hydrogen carbonates, alkalineearth metal-C₁-C₄-alcoholates, and alkylamines with a total of 2 to 12carbon atoms; c) at least one trihydrocarbylphosphane; and d) at leastone organic reducing agent that is different from the remainingcomponents that are used in the method.
 2. The method of claim 1,wherein the at least one palladium compound is selected from the groupconsisting of alkali tetrahalogenopalladates(II), ammoniumtetrahalogenopalladates(II), alkali hexahalogenopalladates(IV), ammoniumhexahalogenopalladates(IV), palladium(II) halides, palladium(II)nitrate, palladium(II) sulfate,bis(trihydrocarbylphosphane)palladium(II) dihalides, Pd(COD)Cl₂,Pd(CH₃CN)₂Cl₂, Pd(C₆H₅CN)₂Cl₂, and palladium(II) acetate.
 3. The methodof claim 1, wherein the palladium compound is PdCl₂.
 4. The method ofclaim 1, wherein the at least one polar-aprotic solvent is selected fromthe group consisting of tertiary carboxylic acid amides, sulfoxides,ketones, lactones, lactams, nitriles, urea derivatives, sulfones,carboxylic acid esters, and carbonic acid esters.
 5. The method of claim1, wherein the at least one polar-aprotic solvent is selected from thegroup consisting of DMF, DMSO, acetone, gamma-butyrolactone,N-methyl-2-pyrrolidone, acetic acid ethyl ester, and acetonitrile. 6.The method of claim 1, wherein the at least one organic reducing agentis selected from the group consisting of ascorbic acid, formic acid, aswell as alkali metal, alkaline earth metal and ammonium salts of saidacids, phenols with a reducing effect, phenol derivatives with areducing effect, and sugars with a reducing effect.
 7. The method ofclaim 1, wherein the at least one organic reducing agent is selectedfrom ascorbic acid and formic acid.
 8. The method of claim 1, whereinthe three hydrocarbyl residues of the at least onetrihydrocarbylphosphane are selected from the group consisting ofunsubstituted aryl residues, substituted aryl residues, open chain alkylresidues, and cyclic alkyl residues, in any combination thereof.
 9. Themethod of claim 1, wherein the at least one trihydrocarbylphosphane istriphenylphosphane.
 10. The method of claim 1, wherein 50 to 100% byweight of the organic solvent consists of at least one polar-aproticsolvent selected from the group consisting of DMF, DMSO, acetone,gamma-butyrolactone, N-methyl-2-pyrrolidone, acetic acid ethyl ester,and acetonitrile, wherein the at least one palladium compound isselected from the group consisting of alkalitetrahalogenopalladates(II), ammonium tetrahalogenopalladates(II),alkali hexahalogenopalladates(IV), ammonium hexahalogenopalladates(IV),palladium(II) halides, palladium(II) nitrate, palladium(II) sulfate,bis(trihydrocarbylphosphane)palladium(II) dihalides, Pd(COD)Cl₂(COD=cyclooctadiene), Pd(CH₃CN)₂Cl₂, Pd(C₆H₅CN)₂Cl₂, and palladium(II)acetate, wherein the at least one base is selected from the groupconsisting of alkali metal hydroxides, alkali metal carbonates, alkalimetal hydrogen carbonates, and triethylamine, and wherein the at leastone organic reducing agent is selected from formic acid and ascorbicacid as well as alkali metal, alkaline earth metal, and ammonium saltsof said acids.
 11. The method of claim 10, wherein the at least onepalladium compound is PdCl₂ and whereby the at least one organicreducing agent is ascorbic acid.
 12. The method of claim 10, wherein theat least one trihydrocarbylphosphane is triphenylphosphane.
 13. Themethod of claim 1, wherein the at least one reducing agent is used,relative to palladium, in an amount equal to 1- to 3-fold of theequivalent amount required for reduction to palladium(0).
 14. The methodof claim 1, wherein 2-4 molar equivalents of base are used per molarequivalent of palladium(II) and 4-8 molar equivalents of base are usedper molar equivalent of palladium(IV).
 15. The method of claim 1,wherein the at least one trihydrocarbylphosphane is used in an amountequal to 4- to 6-fold of the molar equivalent, relative to palladium.16. The method of claim 1, wherein the concentration of the palladiumused, relative to the organic solvent, is in the range of 0.05 mol/L to0.25 mol/L.
 17. The method of claim 1, wherein thetetrakis(trihydrocarbylphosphane)palladium(0) thus produced is separatedas a solid from the liquid phase by filtration, centrifugation ordecanting, the separated solid is washed with water followed by furtherwashing steps with water-miscible alcohols and then with alkanes, ifapplicable, and then the product is dried at reduced pressure.